6-substituted pyrimidine 3-oxides for promoting pigmentation of the skin/hair

ABSTRACT

Pigmentation of human skin and/or hair is promoted by administering to individuals in need of such treatment, advantageously topically, an effective tyrosinase activity-stimulating amount of at least one 6-substituted pyrimidine 3-oxide having the structural formula (I):  
                 
 
     in which R 1  and R 2 , which may be identical or different, are each a hydrogen atom or a C 1 -C 12  alkyl radical; and R 3  and R 4 , which may be identical or different, are each a C 1 -C 12  alkyl radical or, when taken together, form a heterocycle with the nitrogen atom from which they depend, with the proviso that, when R 3  and R 4 , taken together, form a piperidino ring, then at least one of the radicals R 1  or R 2  must be other than a hydrogen atom.

BACKGROUND OF THE INVENTION

[0001] 1. Technical Field of the Invention

[0002] The present invention relates to promoting pigmentation of theskin and/or the hair by administering to individuals in need of suchtreatment at least one pyrimidine 3-oxide derivative, substituted inposition 6, and to pharmaceutical/cosmetic compositions comprising atleast one such derivative.

[0003] 2. Description of the Prior Art

[0004] The color of human hair and skin depends on various factors and,in particular, the seasons of the year, race, sex and age. It isprincipally determined by the concentration of melanin produced by themelanocytes. The melanocytes are specialized cells which synthesizemelanin by means of specific organelles, the melanosomes.

[0005] The synthesis of melanin, or melanogenesis, is particularlycomplex and schematically involves the following principal steps:

[0006] Tyrosine→Dopa→Dopaquinone→Dopachrome→Melanin

[0007] Tyrosinase (monophenol dihydroxyl phenylalanine:oxygenoxidoreductase EC 1.14.18.1) is the essential enzyme involved in thisreaction sequence. It catalyzes, in particular, the reaction for theconversion of tyrosine into dopa (dihydroxyphenylalanine) and thereaction for the conversion of dopa into dopaquinone.

[0008] Although the level of melanin varies from one population toanother, the amount of tyrosinase does not vary significantly and thelevel of messenger RNAs for tyrosinase is identical in white or blackskin. The variations in melanogenesis are thus due to variations in theactivity of tyrosinase.

[0009] It is known that in most populations the brown coloration of theskin and the maintenance of a constant color of the hair are importantaspirations.

[0010] There are, moreover, pigmentation diseases such as, for example,vitiligo, which is an autoimmune disease characterized by the appearanceof white patches on the skin, associated with a pigmentation defect.

[0011] Genuine need therefore exists for products which facilitateand/or improve pigmentation of the skin and/or the hair.

[0012] In this respect, many artificial dyeing techniques have beenproposed to this art, by supplying external dyes that are intended toimpart to the skin and/or the hair the closest possible color to theirnatural color, as well as natural dyeing techniques by stimulation ofthe natural pigmentation route.

[0013] Although, admittedly, excellent results are obtained by thesolutions proposed in the prior art, it nevertheless remains that thestimulation of pigmentation of the skin and/or the hair via the naturalroute remains the ideal route for pigmentation.

[0014] In this regard, WO-A-95/17,161, WO-95/11,003, WO-A-95/01,773,WO-A-94/04,674, WO-A-94/04,122, EP-A-585,018, WO-A-93/10,804,WO-A-92/20,322 and WO-A-91/07,945 describe varied techniques forattaining the desired results, such as administration of compositionscontaining phosphodiesterase inhibitors, prostaglandins, DNA fragments,or tyrosine derivatives or, alternatively, administration of plantextracts.

[0015] Often, the compounds used have appreciable side-effects or arecomplex mixtures which have no specificity.

[0016] It has also been suggested, by Rushton and co-workers (Rushton,D. H., et coll., Clin. Exp. Dermatol., 14(1), 40-46 (1989)) thatMinoxidil, or 2,4-diamino-6-piperidinopyrimidine 3-oxide, can exhibit astimulatory effect on hair pigmentation in bald men treated with thiscompound.

[0017] “Minoxidil” is known for its anti-hypertensive effects and forits capacity to promote hair growth. These properties are described inU.S. Pat. No. 4,596,812.

[0018] Although Minoxidil remains the reference compound in the field ofhair growth, it has appreciable side-effects which complicate its use.

[0019] Thus, developing novel active agents which affect skin and/orhair pigmentation without eliciting undesirable side-effects remains amajor research objective.

SUMMARY OF THE INVENTION

[0020] Accordingly, a major object of the present invention is theprovision of novel compounds to promote pigmentation of the skin and/orthe hair, while at the same time limiting deleterious side effects.

[0021] Briefly, it has now unexpectedly been determined that certainpyrimidine 3-oxide derivatives, substituted in position 6, display anactivating effect on tyrosinase which is similar or superior to that ofMinoxidil.

[0022] The subject compounds according to the invention have thefollowing structural formula (I):

[0023] in which R₁ and R₂, which may be identical or different, are eacha hydrogen atom or a C₁-C₁₂ alkyl radical; and R₃ and R₄, which may beidentical or different, are each a C₁-C₁₂ alkyl radical or, when takentogether, form a heterocycle with the nitrogen atom from which theydepend, with the proviso that, when R₃ and R₄, taken together, form apiperidino ring, then at least one of the radicals R₁ or R₂ must beother than a hydrogen atom.

DETAILED DESCRIPTION OF BEST MODE AND SPECIFIC/PREFERRED EMBODIMENTS OFTHE INVENTION

[0024] More particularly according to the present invention, featuredare cosmetic/pharmaceutical compositions comprising, as the activeprinciple, an effective amount of at least one pyrimidine 3-oxidecompound, substituted in position 6 and having the formula (I), forpromoting pigmentation of the skin and/or the hair.

[0025] The present invention also features cosmetic/pharmaceuticalcompositions comprising, as the active principle, an effective amount ofat least one pyrimidine 3-oxide compound, substituted in position 6 andhaving the formula (I), for stimulating tyrosinase activity, andformulated into a cosmetically/pharmaceutically acceptable vehicle,diluent or carrier therefor.

[0026] This invention also features use of the optical isomers of thesubject compounds, singly or in admixture in all proportions, as well asuse of the acyl derivatives or pharmaceutically acceptable saltsthereof.

[0027] According to the invention, by the expression “C₁-C₁₂ alkylradical” is intended linear or branched C₁-C₁₂ alkyl radicals,optionally substituted with at least one hydroxyl radical or benzylradical and, in particular, the optionally substituted linear orbranched methyl, ethyl, propyl, butyl, pentyl, hexyl or benzyl radicals.

[0028] By the term “heterocycle” is intended any saturated orunsaturated ring member containing at least one nitrogen atom,including, in particular, aziridino, azetidino, pyrrolidino, piperidino,hexamethyleneimino, heptamethyleneimino, octamethyleneimino,tetrahydropyridino, dihydropyridino, pyrrole, pyrazole, imidazole,triazole, 4-alkylpiperazino, morpholino or thiomorpholino rings members.

[0029] According to the invention, the heterocycle is preferably apiperidino ring member.

[0030] Of course, the derivatives of formula (I) may be administeredeither alone or as a mixture in any proportion.

[0031] By the term “tyrosinase” is intended any enzyme exhibitingtyrosinase activity, it being possible for this enzyme to exhibit otherenzymatic activities.

[0032] The tyrosinase activity may be defined as the enzymatic activitywhich catalyzes the oxidation of tyrosine resulting in the formation ofthe melanin precursor: dopaquinone.

[0033] Many pyrimidine derivatives substituted in position 6 andtechniques for the synthesis thereof are known to this art. Particularlyexemplary are those described in EP-A-353,123, EP-A-356,271,EP-A-408,422, EP-A-420,707, EP-A-427,625, EP-A-459,890, EP-A-519,819,EP-A-522,964, EP-A-525,964 and EP-A-540,629.

[0034] Among the 6-substituted pyrimidine 3-oxide compounds according tothe invention, particularly preferred are:

[0035] 2,4 bis-methylamino-6-dimethylaminopyrimidine 3-oxide,

[0036] 2,4 bis-ethylamino-6-dimethylaminopyrimidine 3-oxide,

[0037] 2,4-bis-propylamino-6-dimethylaminopyrimidine 3-oxide,

[0038] 2,4-bis-propylamino-6-piperidinopyrimidine 3-oxide,

[0039] 2-amino-4-methylamino-6-piperidinopyrimidine 3-oxide,

[0040] 2-amino-4-propylamino-6-piperidinopyrimidine 3-oxide,

[0041] 2-amino-4-hexylamino-6-piperidinopyrimidine 3-oxide,

[0042] 2-amino-4-benzylamino-6-piperidinopyrimidine 3-oxide,

[0043] 2-amino-4-(2-hydroxyethylamino)-6-piperidinopyrimidine 3-oxide,

[0044] 2-amino-4-propylamino-6-dimethylaminopyrimidine 3-oxide,

[0045] 2-amino-4-butylamino-6-dimethylaminopyrimidine 3-oxide,

[0046] 2-amino-4-isopropylamino-6-dimethylaminopyrimidine 3-oxide.

[0047] Even more preferred are:

[0048] 2-amino-4-propylamino-6-dimethylaminopyrimidine 3-oxide,

[0049] 2-amino-4-methylamino-6-piperidinopyrimidine 3-oxide,

[0050] 2,4-bis-propylamino-6-dimethylaminopyrimidine 3-oxide,

[0051] 2,4-bis-propylamino-6-piperidinopyrimidine 3-oxide,

[0052] 2,4-bis-methylamino-6-dimethylaminopyrimidine 3-oxide,

[0053] 2,4-bis-ethylamino-6-dimethylaminopyrimidine 3-oxide.

[0054] The amount of compound required to promote pigmentation of theskin and/or the hair is an amount required to stimulate the tyrosinaseactivity. This amount is, of course, dependent on the nature of thederivative and on the nature of the tyrosinase in question and may varyover a wide range.

[0055] In order to provide an order of magnitude, if the derivativeaccording to the invention is used in a cosmetic composition, the amountof derivative which is advantageously used may range from 0.01% to 20%of the total weight of the composition and preferably from 0.1% to 10%of the total weight of the composition.

[0056] In order to provide an order of magnitude, if the derivativeaccording to the invention is used in a pharmaceutical composition, theamount of derivative which is advantageously used may range from 1% to30% of the total weight of the composition and preferably from 2% to 15%of the total weight of the composition.

[0057] The compositions according to the invention are essentiallyintended to promote pigmentation of the skin and/or the hair and tostimulate the endogenous tyrosinase activity of the skin and/or thehair.

[0058] Thus, this invention features a cosmetic or pharmaceuticalcomposition comprising at least one derivative corresponding to thestructural formula (I) and at least one substrate of at least one enzymeexhibiting a tyrosinase activity.

[0059] Among the substrates which are suitable according to theinvention, exemplary are tyrosine and derivatives thereof, and3,4-dihydroxy-a-phenylalanine (DOPA).

[0060] It is possible to combine the derivative of formula (I) and thesubstrate in a single composition. However, other specific embodimentsare intended, in particular the derivative and the substrate may beadministered simultaneously, separately or variously over time.

[0061] Thus, the present invention features a product comprising atleast one derivative corresponding to the structural formula (I) and atleast one substrate of at least one enzyme exhibiting a tyrosinaseactivity, as a combination product for a simultaneous or separate use,or for use divided or spread out over time, in order to promotepigmentation of the skin and/or the hair.

[0062] In a specific embodiment, the derivative and the substrate may bepackaged separately in the form of a kit whose components will be mixedtogether at the time of use.

[0063] The invention thus also features a kit comprising at least onederivative corresponding to the structural formula (I) and at least onesubstrate of at least one enzyme exhibiting a tyrosinase activity forsimultaneous or separate use, or for use spread out over time, in orderto promote pigmentation of the skin and/or the hair.

[0064] The compositions according to the invention may be ingested,injected or topically applied to the skin (onto any area of body skin)or the hair. According to the particular mode of administration, thecompositions according to the invention may be in any pharmaceuticalform normally used.

[0065] For topical application to the skin, the composition may be inthe form, in particular, of an aqueous or oily solution or of adispersion of the lotion or serum type, emulsions of liquid orsemi-liquid consistency of the milk type, obtained by dispersion of afatty phase in an aqueous phase (O/W) or, conversely, (W/O), orsuspensions or emulsions of soft consistency of the cream or aqueous oranhydrous gel type, or alternatively microcapsules or microparticles, orvesicle dispersions of the ionic and/or nonionic type. Thesecompositions are formulated according to the usual techniques.

[0066] They may also be applied to the hair in the form of aqueous,alcoholic or aqueous-alcoholic solutions, or in the form of creams,gels, emulsions or mousses or alternatively in the form of aerosolcompositions also comprising a propellant under pressure.

[0067] The compositions according to the invention may also becompositions for hair care, and in particular a shampoo, a hair-settinglotion, a treating lotion, a styling cream or gel, a composition fordyeing (in particular oxidation dyeing) optionally in the form of dyeshampoos, restructuring lotions for the hair, a permanent-wavecomposition (in particular a composition for the first stage of apermanent-wave operation), a lotion or gel to combat hair loss, anantiparasitic shampoo, etc.

[0068] For injection, the subject compositions may be formulated as anaqueous or oily lotion or as a serum, and for ingestion, they may beformulated as capsules, granules, syrups or tablets.

[0069] The amounts of the various constituents of the compositionsaccording to the invention are those conventionally used in theparticular fields under consideration.

[0070] The compositions according to the invention may also beformulated as solid preparations constituting cleansing soaps or bars.

[0071] The subject compositions may also be packaged in the form of anaerosol composition, also comprising a propellant under pressure.

[0072] When the composition is an emulsion, the proportion of the fattyphase advantageously ranges from 5% to 80% by weight, and preferablyfrom 5% to 50% by weight, relative to the total weight of thecomposition. The oils, waxes, emulsifiers and co-emulsifiers formulatedinto the composition in emulsion form are selected from among thoseconventionally used in the cosmetics field. The emulsifier and theco-emulsifier are advantageously present in the composition in aproportion ranging from 0.3% to 30% by weight, and preferably from 0.5to 20% by weight, relative to the total weight of the composition. Theemulsion may also contain lipid vesicles.

[0073] When the composition is an oily gel or solution, the fatty phasemay constitute more than 90% of the total weight of the composition.

[0074] In known manner, the cosmetic compositions may also containadditives and adjuvants that are conventional in the cosmetics field,such as hydrophilic or lipophilic gelling agents, hydrophilic orlipophilic additives, preservatives, antioxidants, solvents, fragrances,fillers, UV-screening agents, odor absorbers and colorants anddyestuffs. The amounts of these various additives and adjuvants arethose conventionally used in the cosmetics field, and, for example,advantageously range from 0.01 to 10% of the total weight of thecomposition. Depending on their nature, these additives and adjuvantsmay be introduced into the fatty phase, into the aqueous phase and/orinto the lipid spherules.

[0075] Exemplary such oils or waxes according to the invention includemineral oils (liquid petroleum jelly), plant oils (liquid fraction ofkarite butter, sunflower oil), animal oils (perhydrosqualene), syntheticoils (purcellin oil), silicone oils or waxes (cyclomethicone) and fluorooils (perfluoropolyethers), beeswax, carnauba wax or paraffin wax. Fattyalcohols and fatty acids (stearic acid) may be added to these oils.Exemplary emulsifiers according to the invention include glycerylstearate, polysorbate 60 and the mixture of PEG-6/PEG-32/glycol stearatemarketed under the trademark Tefose^(R) 63 by Gattefosse.

[0076] And exemplary solvents include the lower alcohols and, inparticular, ethanol and isopropanol, and propylene glycol.

[0077] Exemplary hydrophilic gelling agents according to the inventioninclude carboxyvinyl polymers (carbomer), acrylic copolymers such ascopolymers of acrylates/alkyl acrylates, polyacrylamides,polysaccharides such as hydroxypropylcellulose, natural gums and clays,and exemplary lipophilic gelling agents include modified clays such asbentones, metal salts of fatty acids such as aluminum stearates andhydrophobic silica, ethylcellulose and polyethylene.

[0078] The subject compositions may contain other hydrophilic activeagents such as proteins or protein hydrolysates, amino acids, polyols,urea, allantoin, sugars and sugar derivatives, water-soluble vitamins,plant extracts and hydroxy acids.

[0079] Representative lipophilic active agents include retinol (vitaminA) and derivatives thereof, tocopherol (vitamin E) and derivativesthereof, essential fatty acids, ceramides, essential oils and salicylicacid and derivatives thereof.

[0080] According to the invention, the subject compositions may combineat least one compound of formula (I) with other active agents. Amongthese active agents, particularly exemplary are:

[0081] (a) agents which improve activity in respect of regrowth and/orretarding the loss of hair, already known to this art for this activity,such as, for example, nicotinic acid esters, including, in particular,tocopheryl nicotinate, benzyl nicotinate and C₁-C₆ alkyl nicotinatessuch as methyl or hexyl nicotinate, agents which promote the regrowth ofhair, such as those described in EP-0,648,488, assigned to the assigneehereof;

[0082] (b) agents which decrease differentiation and/or proliferation,such as retinoic acid and isomers thereof, retinol and esters thereof,vitamin D and derivatives thereof, and estrogens such as estradiol;

[0083] (c) antibacterial agents such as clindamycin phosphate,erythromycin or antibiotics of the tetracyclin class;

[0084] (d) antiparasitic agents, in particular metronidazole, crotamitonor pyrethroids;

[0085] (e) antifungal agents, in particular compounds of the imidazoleclass such as econazole, ketoconazole or miconazole or salts thereof,polyene compounds such as amphotericin B, compounds of the allylaminefamily such as terbinafine, or, alternatively, octopirox;

[0086] (f) antiviral agents such as acyclovir;

[0087] (g) steroidal anti-inflammatory agents such as hydrocortisone,betamethasone valerate or clobetasol propionate, or nonsteroidalanti-inflammatory agents such as, for example, ibuprofen and saltsthereof, diclofenac and salts thereof, acetylsalicylic acid,acetaminophene or glycyrrhizic acid;

[0088] (h) anaesthetics such as lidocaine hydrochloride and derivativesthereof;

[0089] (i) antipruriginous agents such as thenaldine, trimeprazine orcyproheptadine;

[0090] (j) keratolytic agents such as α- and β-hydroxycarboxylic acidsor β-ketocarboxylic acids, and the salts, amides or esters thereof and,more particularly, hydroxy acids such as glycolic acid, lactic acid,salicylic acid, citric acid and fruit acids in general, and5-n-octanoylsalicylic acid;

[0091] (k) anti-free-radical agents such as α-tocopherol and estersthereof, superoxide dismutases, certain metal-chelating agents orascorbic acid and esters thereof;

[0092] (l) antiseborrhoeic agents such as progesterone;

[0093] (m) antidandruff agents such as octopirox or zinc pyrithione;

[0094] (n) antiacne agents such as retinoic acid or benzoyl peroxide;

[0095] (o) extracts of plant or bacterial origin.

[0096] Other such compounds include, for example, Diazoxide,Spiroxazone, phospholipids such as lecithin, linoleic acid, linolenicacid, salicylic acid and derivatives thereof described in FR-2,581,542,e.g., salicylic acid derivatives bearing an alkanoyl group having from 2to 12 carbon atoms in position 5 of the benzene ring, hydroxycarboxylicor ketocarboxylic acids and their esters, lactones and theircorresponding salts, anthralin, carotenoids, eicosatetraynoic andeicosatriynoic acids or the esters and amides thereof, vitamin D andderivatives thereof, and extracts of plant or bacterial origin.

[0097] Thus, in a preferred embodiment the subject compositionsaccording to the invention also comprise at least one active agentselected from among antibacterial agents, antiparasitic agents,antifungal agents, antiviral agents, anti-inflammatory agents,antipruriginous agents, anaesthetics, keratolytic agents,anti-free-radical agents, antiseborrhoeic agents, antidandruff agents,antiacne agents and/or agents for reducing skin differentiation and/orproliferation and/or pigmentation, and extracts of plant or bacterialorigin.

[0098] The subject compositions may also comprise at least one activeagent as described above is in liposomal form, in particular asdescribed in WO-94/22468, filed Oct. 13, 1994 by Anti-Cancer Inc. Thus,the compound encapsulated in the liposomes may be delivered selectivelyto the hair follicle.

[0099] The pharmaceutical compositions according to the invention may beadministered parenterally, systemically, enterally or topically. Thesepharmaceutical compositions are preferably administered topically.

[0100] In order to determine the activity of the pyrimidine derivativessubstituted in position 6, the simple and rapid technique is employedthat entails measurement by incubating an optionally purified tyrosinaseand one of its substrates in a suitable medium in the presence of a testcompound, and then comparing the measurements taken with the results ofidentical measurements taken during the incubation of optionallypurified tyrosinase with one of its substrates in the absence of thetest compound.

[0101] In order to further illustrate the present invention and theadvantages thereof, the following specific examples are given, it beingunderstood that same are intended only as illustrative and in nowiselimitative.

EXAMPLE 1

[0102] Modulation of Tyrosinase Activity by Pyrimidine 3-oxideDerivatives, Substituted in Position 6:

[0103] General Principles of the Measurement:

[0104] A purified tyrosinase was incubated in the presence of one of itssubstrates in a suitable medium, in the presence or absence of apyrimidine 3-oxide derivative, substituted in position 6. The activityof the enzyme was evaluated by measuring the amount of a product ofconversion of the substrate formed during the reaction. The resultobtained in the presence of a derivative was compared with the resultobtained in the absence of a derivative.

[0105] This comparison made it possible to evaluate the influence of aderivative on the activity of the enzyme.

[0106] Preparation for the Measurements:

[0107] The substrate used was L-tyrosine (marketed by Sigma), a stocksolution of which was prepared in phosphate-buffered saline (PBS) at aconcentration of 0.5 mM.

[0108] The enzyme used was a purified fungal tyrosinase (EC 1.14.18.1)marketed by Sigma. A stock solution of this enzyme was prepared in PBSat a concentration of 5 mg/ml, which represents a concentration of about19,500 international units of tyrosinase per milliliter.

[0109] The product of conversion of the tyrosine by tyrosinase,dopachrome, was measured by spectrophotometry at a wavelength of 475 nmusing a Perkin Elmer type apparatus.

[0110] The derivative to be tested was prepared in solution in PBScontaining 1% ethanol at a concentration of 1 mM.

[0111] Measurements:

[0112] The following reagents were mixed together in a spectrophotometercell:

[0113] 500 μl of tyrosine solution,

[0114] 390 μl of phosphate buffer,

[0115] 10 μl of fungal tyrosinase solution,

[0116] 100 μl of solution of test derivative or of PBS/1% ethanol(control).

[0117] The mixture was then incubated at a temperature of 37° C. and thedopachrome formed was measured continuously for at least 30 minutes.

[0118] Results:

[0119] The results obtained are expressed as a % of activation of thetyrosinase activity relative to the value obtained with the control (inthe absence of derivative). Derivatives Activation Control  0%2,4-diamino-6-piperidinopyrimidine 3-oxide (Minoxidil) 41%2,4-bis-methylamino-6-dimethylaminopyrimidine 3-oxide 61%2,4-bis-ethylamino-6-dimethylaminopyrimidine 3-oxide 60%2,4-bis-propylamino-6-dimethylaminopyrimidine 3-oxide 55%2,4-bis-propylamino-6-piperidinopyrimidine 3-oxide 57%2-amino-4-methylamino-6-piperidinopyrimidine 3-oxide 50%2-amino-4-propylamino-6-piperidinopyrimidine 3-oxide 46%2-amino-4-hexylamino-6-piperidinopyrimidine 3-oxide 47%2-amino-4-benzylamino-6-piperidinopyrimidine 3-oxide 45%2-amino-4-(2-hydroxyethylamino)-6-piperidinopyrimidine 43% 3-oxide2-amino-4-propylamino-6-dimethylaminopyrimidine 3-oxide 50%2-amino-4-butylamino-6-dimethylaminopyrimidine 3-oxide 51%2-amino-4-isopropylamino-6-dimethylaminopyrimidine 46% 3-oxide

[0120] These results evidence that the pyrimidine derivatives,substituted in position 6, tested have stimulators properties ontyrosinase which are superior to Minoxidil.

EXAMPLE 2

[0121] Specific Examples of Compositions of the Invention Containing anAryl 2,4-dioxooxazolidine (These Compositions were Formulated via theUsual Techniques Currently Employed in Cosmetics or Pharmacy): Dermalcream: 2,4-Bis-propylamino-6-piperidinopyrimidine 1,000 g 3-oxideCeteareth 30 7,000 g Glyceryl stearate 2,000 g Cetyl alcohol 1,500 gPolydimethylsiloxane 1,500 g Liquid petroleum jelly 15,000 g  Pureglycerol codex 20,000 g  Preservatives q.s. Demineralized water q.s.100,000 g  Dermal lotion to be sprayed:2,4-Bis-methylamino-6-dimethylaminopyrimidine 5,000 g 3-oxide Ethanol30,000 g  Demineralized water q.s. 100,000 g  Lotion for the hair:2,4-Bis-ethylamino-6-dimethylaminopyrimidine 3,000 g 3-oxide Propyleneglycol 30,000 g  Ethylene alcohol 40,500 g  Water qs 100,000 g 

[0122] This lotion was applied to the scalp, once or twice a day, at arate of 1 ml per application. Thickened lotion:2,4-Bis-propylamino-6-piperidinopyrimidine 5,000 g 3-oxide Kawaine 2,000g Hydroxypropylcellulose (Klucel G marketed 3,500 g by Hercules) Ethylalcohol qs 100,000 g 

[0123] This thickened lotion was applied to the scalp, once or twice aday, at a rate of 1 ml per application. Niosomal lotion: Chimexane NL ®0.475 g Cholesterol 0.475 g Monosodium stearoylglutamate 0.050 g2,4-Bis-propylamino-6-piperidinopyrimidine 0.100 g 3-oxide Preservativesqs Dyes qs Fragrance qs Demineralized water qs 100,000 g 

[0124] This lotion was applied to the scalp, once or twice a day, at arate of 1 ml per application. Lotion:2,4-Bis-propylamino-6-dimethylaminopyrimidine 5,000 g  3-oxide Propyleneglycol monomethyl ether (Dowanol PM 20,000 g   marketed by Dow Chemical)Hydroxypropylcellulose (Klucel G marketed by 3000 g Hercules) Ethylalcohol 40,000 g   Minoxidil 2000 g Water qs 100,000 g  

[0125] This thickened lotion was applied to the scalp, once or twice aday, at a rate of 1 ml per application.

[0126] While the invention has been described in terms of variouspreferred embodiments, the skilled artisan will appreciate that variousmodifications, substitutions, omissions, and changes may be made withoutdeparting from the spirit thereof. Accordingly, it is intended that thescope of the present invention be limited solely by the scope of thefollowing claims, including equivalents thereof.

What is claimed is:
 1. A regimen for promoting pigmentation of the skinand/or hair, comprising administering to an individual in need of suchtreatment an effective tyrosinase activity-stimulating amount of atleast one 6-substituted pyrimidine 3-oxide having the structural formula(I):

in which R₁ and R₂, which may be identical or different, are each ahydrogen atom or a C₁-C₁₂ alkyl radical; and R₃ and R₄, which may beidentical or different, are each a C₁-C₁₂ alkyl radical or, when takentogether, form a heterocycle with the nitrogen atom from which theydepend, with the proviso that, when R₃ and R₄, taken together, form apiperidino ring, then at least one of the radicals R₁ or R₂ must beother than a hydrogen atom.
 2. The regimen as defined by claim 1,comprising topically administering said at least one 6-substitutedpyrimidine 3-oxide.
 3. The regimen as defined by claim 1, comprisingsystemically administering said at least one 6-substituted pyrimidine3-oxide.
 4. The regimen as defined by claim 1, said at least one6-substituted pyrimidine 3-oxide comprising2,4-bis-methylamino-6-dimethylaminopyrimidine 3-oxide,2,4-bis-ethylamino-6-dimethylaminopyrimidine 3-oxide,2,4-bis-propylamino-6-dimethylaminopyrimidine 3-oxide,2,4-bis-propylamino-6-piperidinopyrimidine 3-oxide,2-amino-4-methylamino-6-piperidinopyrimidine 3-oxide,2-amino-4-propylamino-6-piperidinopyrimidine 3-oxide,2-amino-4-hexylamino-6-piperidinopyrimidine 3-oxide,2-amino-4-benzylamino-6-piperidinopyrimidine 3-oxide,2-amino-4-(2-hydroxyethylamino)-6-piperidinopyrimidine 3-oxide,2-amino-4-propylamino-6-dimethylaminopyrimidine 3-oxide,2-amino-4-butylamino-6-dimethylaminopyrimidine 3-oxide, or2-amino-4-isopropylamino-6-dimethylaminopyrimidine 3-oxide.
 5. Theregimen as defined by claim 1, said at least one 6-substitutedpyrimidine 3-oxide comprising2-amino-4-propylamino-6-dimethylaminopyrimidine 3-oxide,2-amino-4-methylamino-6-piperidinopyrimidine 3-oxide,2,4-bis-propylamino-6-dimethylaminopyrimidine 3-oxide,2,4-bis-propylamino-6-piperidinopyrimidine 3-oxide,2,4-bis-methylamino-6-dimethylaminopyrimidine 3-oxide, or2,4-bis-ethylamino-6-dimethylaminopyrimidine 3-oxide.
 6. The regimen asdefined by claim 1, comprising coadministering to said individual atleast one substrate of at least one enzyme exhibiting tyrosinaseactivity.
 7. The regimen as defined by claim 6, said at least onesubstrate comprising tyrosine or derivative thereof, or3,4-dihydroxy-α-phenylalanine (DOPA).
 8. A cosmetic/pharmaceuticalcomposition of matter suited for promoting pigmentation of the skinand/or hair, comprising an effective tyrosinase activity-stimulatingamount of at least one 6-substituted pyrimidine 3-oxide having thestructural formula (I):

in which R₁ and R₂, which may be identical or different, are each ahydrogen atom or a C₁-C₁₂ alkyl radical; and R₃ and R₄, which may beidentical or different, are each a C₁-C₁₂ alkyl radical or, when takentogether, form a heterocycle with the nitrogen atom from which theydepend, with the proviso that, when R₃ and R₄, taken together, form apiperidino ring, then at least one of the radicals R₁ or R₂ must beother than a hydrogen atom, formulated into acosmetically/pharmaceutically acceptable vehicle, diluent or carriertherefor.
 9. The cosmetic/pharmaceutical composition as defined by claim8, further comprising at least one substrate of at least one enzymeexhibiting tyrosinase activity.
 10. The cosmetic/pharmaceuticalcomposition as defined by claim 9, said at least one substratecomprising tyrosinase or derivative thereof, or3,4-dihydroxy-α-phenylalanine.
 11. The cosmetic/pharmaceuticalcomposition as defined by claim 8, comprising from 0.01% to 20% byweight of said at least one 6-substituted pyrimidine 3-oxide.
 12. Thecosmetic/pharmaceutical composition as defined by claim 11, comprisingfrom 0.1% to 10% by weight of said at least one 6-substituted pyrimidine3-oxide.
 13. The cosmetic/pharmaceutical composition as defined by claim8, comprising from 1% to 30% by weight of said at least one6-substituted pyrimidine 3-oxide.
 14. The cosmetic/pharmaceuticalcomposition as defined by claim 13, comprising from 2% to 15% by weightof said at least one 6-substituted pyrimidine 3-oxide.
 15. Thecosmetic/pharmaceutical composition as defined by claim 8, comprising asolution, dispersion, lotion, serum, emulsion, milk, cream, gel,microcapsules, microparticles, vesicle dispersion, mousse, aerosol,shampoo, dyeing formulation, permanent-wave, syrup, granules, tablets orsoap.
 16. The cosmetic/pharmaceutical composition as defined by claim 8,further comprising an oil, wax, emulsifier and/or co-emulsifier.
 17. Thecosmetic/pharmaceutical composition as defined by claim 8, furthercomprising at least one active agent selected from among antibacterialagents, antiparasitic agents, antifungal agents, antiviral agents,anti-inflammatory agents, antipruriginous agents, anaesthetics,keratolytic agents, anti-free-radical agents, antiseborrhoeic agents,antidandruff agents, antiacne agents and/or agents for reducing skindifferentiation and/or proliferation and/or pigmentation, and extractsof plant or bacterial origin.
 18. The cosmetic/pharmaceuticalcomposition as defined by claim 8, further comprising at least oneactive agent promoting regrowth and/or retarding loss of hair, and/or atleast one active agent decreasing differentiation and/or proliferation.19. The cosmetic/pharmaceutical composition as defined by claim 8,further comprising at least one hydrophilic or lipophilic gelling agent,hydrophilic or lipophilic additive, preservative, antioxidant, solvent,fragrance, filler, UV-screening agent, odor absorber or colorant ordyestuff.
 20. A kit comprising at least two separate compartments, atleast one of which comprising at least one 6-substituted pyrimidine3-oxide as defined in claim 1, and at least one of which comprising atleast one substrate of at least one enzyme exhibiting tyrosinaseactivity.